The present invention relates in general to pharmaceutical compositions of hepatitis C viral protease inhibitors having improved bioavailability, and methods of using these compositions for inhibiting the replication of the hepatitis C virus (HCV) and for the treatment of an HCV infection.
It has recently been discovered that certain macrocyclic compounds are potent and specific inhibitors of hepatitis C virus (HCV) protease. In particular, compounds of the following formula I have been found to be an especially potent class of inhibitors against the NS3 serine protease of HCV: 
wherein:
 designates an optional bond forming a double bond between positions 13 and 14;
R1 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R5)2, wherein each R5 is independently H, C1-6 alkyl or C3-6 cycloalkyl;
R2 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C6 or 10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four ring heteroatoms selected from nitrogen, oxygen and sulfur;
said cycloalkyl, aryl or Het being optionally substituted with R6, wherein R6 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R7)2, NHxe2x80x94C(O)xe2x80x94R7; or NHxe2x80x94C(O)xe2x80x94NHxe2x80x94R7, wherein each R7 is independently: H, C1-6 alkyl or C3-6 cycloalkyl;
or R6 is NHxe2x80x94C(O)xe2x80x94OR8 wherein R8 is C1-6 alkyl or C3-6 cycloalkyl;
R3 is R9Oxe2x80x94 or R9NHxe2x80x94, wherein R9 is C1-6alkyl or C3-6cycloalkyl;
R4 is H or from one to three substituents on any available carbon atom at positions 8, 9, 10, 11, 12, 13 or 14, said substituent independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio or C1-6 thioalkyl;
See Tsantrizos et al., U.S. application Ser. No. 09/760,946, filed on Jan. 16, 2001, (Boehringer Ingelheim (Canada), Ltd.), which application is herein incorporated by reference in its entirety and is hereinafter referred to as xe2x80x9cTsantrizos et alxe2x80x9d. See also the corresponding WO 00/59929 (Boehringer Ingelheim (Canada) Ltd.).
A structural feature of the compounds of formula I is the presence of the C-terminal carboxylic acid functionality, which was shown to be responsible not only for the potency and reversibility observed for this inhibitor series, but also for the excellent specificity for HCV protease compared to other serine/cysteine proteases. An HCV serine protease inhibitor such as the compounds of formula I would be expected to be an antiviral agent acting via a novel mechanism, i.e. blockage of a virus-encoded essential function for HCV replication. A drug acting through this mechanism should suppress viral replication of all HCV genotypes and therefore provide tangible benefits to patients with chronic hepatitis C.
A common problem among protease inhibitors is that these compounds are lipophilic and have low aqueous solubility. Because of the poor aqueous solubility, conventional solid and liquid pharmaceutical preparations containing these inhibitors may not be absorbed by the patient in a satisfactory manner. Of the various factors that can affect the bioavailability of a drug when administered orally, (which include aqueous solubility, drug absorption through the gastrointestinal tract, dosage strength and first pass effect), aqueous solubility is often found to be among the most important factors. Poorly water soluble compounds often exhibit either erratic or incomplete absorption in the digestive tract, and thus produce a less than desirable response.
The compounds of formula I are zwitterionic and are capable of forming salts with strong acids and bases. Attempts to identify salts of such compounds in solid forms, which would substantially improve aqueous solubility, have not been successful. Various salts of these compounds have been found to be very hygroscopic, reducing the stability of the compounds. In addition, formulations of salts of these compounds generally are prone to precipitation of the parent free-acid in the gastrointestinal tract. Representative compounds of formula I have shown poor bioavailability when administered to animals as an aqueous suspension, suggesting that conventional formulations containing these inhibitors may not be absorbed in a satisfactory manner. Thus, there is a need in the art for pharmaceutical compositions of the formula I compounds having improved bioavailability.
Methods of formulating certain lipophilic macrocyclic compounds into pharmaceutical formulations have been previously reported. For example, Cavanak, U.S. Pat. No. 4,388,307, discloses the preparation of emulsified formulations of commercially available cyclosporins, and Hauer et. al, U.S. Pat. No. 5,342,625, and Meizner et al. WO 93/20833 disclose the preparation of cyclosporin microemulsions and microemulsion pre-concentrates. Komiya et. al, U.S. Pat. No. 5,504,068, further discloses the preparation of an enhanced topical formulations of cyclosporin.
Examples of xe2x80x9cself-emulsifyingxe2x80x9d formulations of lipophilic compounds include Lipari et al, WO 96/36316, which discloses a self-emulsifying pre-concentrate comprising a lipophilic compound, d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and a lipophilic phase. Gao et al., U.S. Pat. No. 6,121,313 discloses a self-emulsifying formulation of a pyranone protease inhibitor comprising the pyranone compound, a mixture of mono- and di-glycerides, one or more solvents and one or more surfactants; and Gao et al, U.S. Pat. No. 6,231,887 B1 discloses a self-emulsifying formulation of a pyranone protease inhibitor comprising the pyranone compound, an amine, one or more solvents and one or more surfactants.
Yu et. al U.S. Pat. Nos. 5,360,615 and 5,071,643 disclose the preparation of a solvent system for enhancing the solubility of acidic, basic or amphoteric compounds by partial ionization comprising a mixture of polyethylene glycol, hydroxide or hydrogen ion, and water. Morton et al U.S. Pat. No. 5,376,688 discloses solutions of acidic, basic or amphoteric pharmaceutical agents comprising the pharmaceutical agent, an ionic species and a solvent system. Bhagwat et. al U.S. Pat. No. 6,056,977 teaches the use of polysaccharide based matrix for sustained release of a sulfonylurea.
Despite these advances, there continues to be a need in the art for oral pharmaceutical compositions of the zwitterionic compounds of formula I having improved bioavailability.
The present invention overcomes the aforementioned problems by providing pharmaceutical compositions of the formula I compounds having improved bioavailability as compared to conventional pharmaceutical formulations. In particular, specific compositions of the present invention have demonstrated excellent in vitro dissolution profiles and have achieved marked increases in bioavailability as compared to conventional pharmaceutical formulations.
The pharmaceutical compositions of the present invention cover a wide variety of types of compositions, but all comprise a compound of formula I together with one or more pharmaceutically acceptable amines. The compositions of the present invention may include one or more additional ingredients depending on the type of composition contemplated, e.g., pharmaceutically acceptable solvents, surfactants, oils, polymers, etc., as will be discussed in more detail below. The present invention is also directed to the methods of manufacturing these compositions, as described hereinafter.
In a general embodiment, the pharmaceutical composition of the present invention comprises:
(a) a compound of formula (I): 
wherein:
 designates an optional bond forming a double bond between positions 13 and 14;
R1 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R5)2, wherein each R5 is independently H, C1-6 alkyl or C3-6 cycloalkyl;
R2 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C6 or 10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four ring heteroatoms selected from nitrogen, oxygen and sulfur;
said cycloalkyl, aryl or Het being optionally substituted with R6,
wherein R6 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R7)2, NHxe2x80x94C(O)xe2x80x94R7; or NHxe2x80x94C(O)xe2x80x94NHxe2x80x94R7, wherein each R7 is independently: H, C1-6 alkyl or C3-6 cycloalkyl;
or R6 is NHxe2x80x94C(O)xe2x80x94OR8 wherein R8 is C1-6 alkyl or C3-6 cycloalkyl;
R3 is R9Oxe2x80x94 or R9NHxe2x80x94, wherein R9 is C1-6alkyl or C3-6cycloalkyl;
R4 is H or from one to three substituents on any available carbon atom at positions 8, 9, 10, 11, 12, 13 or 14, said substituent independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio or C1-6 thioalkyl; or a tautomer thereof;
(b) about 0.1 to 10% by weight of a pharmaceutically acceptable amine or a mixture of pharmaceutically acceptable amines; and
(c) one or more pharmaceutically acceptable oils, carriers or hydrophilic solvents;
and when (c) is one or more pharmaceutically acceptable oils, the pharmaceutical composition further comprises:
(d) optionally one or more pharmaceutically acceptable hydrophilic solvents;
(e) optionally one or more pharmaceutically acceptable polymers; and
(f) optionally one or more pharmaceutically acceptable surfactants;
and when (c) is one or more pharmaceutically acceptable carriers, the pharmaceutical composition further comprises:
(d) optionally one or more pharmaceutically acceptable surfactants.
Another important aspect of the present invention involves a method of inhibiting the replication of hepatitis C virus by exposing the virus to a hepatitis C viral NS3 protease-inhibiting amount of a pharmaceutical composition of the present invention.
Another important aspect of the present invention involves a method of treating a hepatitis C viral infection in a mammal by administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention.